title: A new generation of peptide-based inhibitors targeting HIV-1 reverse transcriptase conformational flexibility.
abstract: The biologically active form of human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT) is a heterodimer. The formation of RT is a two-step mechanism, including a rapid protein-protein interaction "the dimerization step," followed by conformational changes "the maturation step," yielding the biologically active form of the enzyme. We have previously proposed that the heterodimeric organization of RT constitutes an interesting target for the design of new inhibitors. Here, we propose a new class of RT inhibitors that targets protein-protein interactions and conformational changes involved in the maturation of heterodimeric reverse transcriptase. Based on a screen of peptides derived from the thumb domain of this enzyme, we have identified a short peptide P(AW) that inhibits the maturation step and blocks viral replication at subnanomolar concentrations. P(AW) only binds dimeric RT and stabilizes it in an inactive/non-processive conformation. From a mechanistic point of view, P(AW) prevents proper binding of primer/template by affecting the structural dynamics of the thumb/fingers of p66 subunit. Taken together, these results demonstrate that HIV-1 RT maturation constitutes an attractive target for AIDS chemotherapeutics.
authors.affiliation: Centre de Recherches de Biochimie Macromoláculaire, Department of Molecular Biophysics & Therapeutic, UMR-5237 CNRS-UM2-UM1, 1919 Route de Mende, Montpellier 34293 and the SPI-BIO Commissariat á l'ánergie Atomique, Pharmacologie des Rátrovirus, 18 Route du Panorama, BP6, Fontenay aux Roses 9226, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Agopian
authors.affiliation: Centre de Recherches de Biochimie Macromoláculaire, Department of Molecular Biophysics & Therapeutic, UMR-5237 CNRS-UM2-UM1, 1919 Route de Mende, Montpellier 34293 and the SPI-BIO Commissariat á l'ánergie Atomique, Pharmacologie des Rátrovirus, 18 Route du Panorama, BP6, Fontenay aux Roses 9226, France.
authors.forename: Edwige
authors.initials: E
authors.lastname: Gros
authors.affiliation: Centre de Recherches de Biochimie Macromoláculaire, Department of Molecular Biophysics & Therapeutic, UMR-5237 CNRS-UM2-UM1, 1919 Route de Mende, Montpellier 34293 and the SPI-BIO Commissariat á l'ánergie Atomique, Pharmacologie des Rátrovirus, 18 Route du Panorama, BP6, Fontenay aux Roses 9226, France.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Aldrian-Herrada
authors.affiliation: Centre de Recherches de Biochimie Macromoláculaire, Department of Molecular Biophysics & Therapeutic, UMR-5237 CNRS-UM2-UM1, 1919 Route de Mende, Montpellier 34293 and the SPI-BIO Commissariat á l'ánergie Atomique, Pharmacologie des Rátrovirus, 18 Route du Panorama, BP6, Fontenay aux Roses 9226, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bosquet
authors.affiliation: Centre de Recherches de Biochimie Macromoláculaire, Department of Molecular Biophysics & Therapeutic, UMR-5237 CNRS-UM2-UM1, 1919 Route de Mende, Montpellier 34293 and the SPI-BIO Commissariat á l'ánergie Atomique, Pharmacologie des Rátrovirus, 18 Route du Panorama, BP6, Fontenay aux Roses 9226, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.affiliation: Centre de Recherches de Biochimie Macromoláculaire, Department of Molecular Biophysics & Therapeutic, UMR-5237 CNRS-UM2-UM1, 1919 Route de Mende, Montpellier 34293 and the SPI-BIO Commissariat á l'ánergie Atomique, Pharmacologie des Rátrovirus, 18 Route du Panorama, BP6, Fontenay aux Roses 9226, France. Electronic address: gilles.divita@crbm.cnrs.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Divita
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D010455:Peptides; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase